B-cell biology and DNA repair

_________________________________________

Alexandre Orthwein, M.Sc., Ph.D.

Alexandre Orthwein is an independent investigator at the Lady Davis Institute and an Assistant Professor in the Department of Oncology at McGill University. He received his M.Sc. from the University of Montreal in the laboratory of Dr. Eric A. Cohen at the IRCM in Montreal, Canada. He subsequently joined the laboratory of Dr. Javier M. Di Noia at the IRCM and received his Ph.D. from the University of Montreal. There, Dr. Orthwein developed a strong interest in B-cell biology and malignancies by studying a critical mutagenic enzyme called Activation Induced Deaminase (AID). This cytidine deaminase induces point mutations and DNA double-strand breaks (DSBs) to diversify the Immunoglobulin genes that encode for antibodies. Due to its oncogenic potential, AID needs to be tightly regulated and Dr. Orthwein showed that the HSP90 molecular chaperoning pathway controls AID protein stability in the cytoplasm and antibody diversification. He also showed that modulation of AID levels by inhibiting HSP90 has useful implications for the treatments of chronic myeloid leukemia.

Subsequently, Dr. Orthwein conducted his postdoctoral training in the laboratory of Dr. Daniel Durocher at Mount Sinai Hospital in Toronto and focused on the interplay between the cell cycle and the signalling/repair of DSBs. There, he elucidated how mitotic cells inhibit the DSB response to preserve genomic stability. He discovered that reactivation of DSB repair specifically in mitosis is deleterious to cells and leads to extensive chromosome fusions. He was awarded the Young Canadian Cell Biologist of the Year 2014 by the Canadian Society for Molecular Biosciences for this work. More recently, he identified a novel regulatory pathway limiting DSB repair by homologous recombination in G1 phase of the cell cycle.

At the Lady Davis Institute and with the financial support of the Cole Foundation, Dr. Orthwein is now investigating how B-cells control DNA repair pathways to allow for antibody diversification but limit carcinogenesis. By understanding B-cell biology and DNA repair, he hopes to translate this knowledge into better care for patients affected by B-cell malignancies through the development of targeted cancer prevention and treatment strategies.

For more information on the laboratory of Dr. Alexandre Orthwein, please visit: www.orthweinlab.com